Method of use

ABSTRACT

A method for treatment of sleeping disturbance to obtain improvement of sleeping, wherein a therapeutically effective dose of esomeprazole or an alkaline salt thereof is administered to a patient suffering therefrom. The method is applicable for instance in patients suffering from gastroesophagal diseases (GERD).

FIELD OF INVENTION

The present invention relates to a method of treating sleepingdisturbance in patients by administration ofS-5-methoxy-2-[[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,known as esomeprazole, to obtain an improvement in sleeping and on amore general level symptom relief and health-related quality of life.

BACKGROUND OF THE INVENTION

Gastric contents, frequently acidic, may give rise to dyspepticsymptoms. Most common symptoms are heartburn, acid regurgitation andchest pain. Other symptoms such as coughing, hoarsness, wheezing andasthma-like symptoms are also encountered. Heartburn is commonlyreported. Up to 44% of Americans have heartburn at least monthly.Patients with these dyspeptic symptoms are said to suffer fromgastro-esophageal reflux disease (GERD). It is estimated that about 25%of GERD sufferers seek medical advise and among these between 35% and70% have none or minimal evidence of endoscopic esophagitis. More thanone-third of the patents with heartburn report weekly symptoms and mostpatients have had their symptoms for more than one year. The primaryimpact of GERD is on a patient's day to day functioning and quality oflife. Sleep disturbance is commonly encountered.

It is to be noted that dyspepsia is a common disorder and patients areseeing both gastroenterologists and general practicians because of it.Symtoms associated with dyspepsia are for instance upper abdominalpain/discomfort, heartburn, indigestion and sour stomach.

Therapeutic agents effective in the treatment of dyspepsia and GERDinclude gastric acid suppressing agents, such as H₂ receptor antagonistsand proton pump inhibitors. Other agents of interest areantacids/alginates and prokinetic agents. These agents can bedistinguished by their mechanisms of action, safety profile,pharmacokinetics and indications.

Antacid agents and alginates may be used alone in the treatment ofheartburn. They have a short duration of action but are seen asinexpensive and safe. Antacid agents work locally through aneutralisation of gastric acid. Alginates further give some mechanicalprotection against reflux or gastric acid into the esophagasus. The mainadvantages of antacid agents and alginates are, that they provide fastrelief of symtoms. The main disadvantage of antacid agents and alginatesis that, dosing has to be repeated frequently to keep the patients freeof symtoms, further that antacids in many cases do not provide symtomresolution, i.e. complete relief of symtoms.

H₂ receptor antagonists are widely prescribed for reducing gastric acidsecretion systemically. Proton pump inhibitors, such as omeprazole,lansoprazole and pantoprazole are rapidly taking share from H₂ receptorantagonists. Omeprazole is known to offer significant gain over H₂receptor antagonists in terms of symptom resolution, healing andprevention of relapse.

Proton pump inhibitors have in clinical studies been proven to be veryeffective in providing symtom resolution (usually within 24-48 hours) inpatients with dyspepsia associated with gastric ulcers, duodenal ulcers,reflux esophagitis and gastroesophageal reflux without esophagitis. Itis for instance established that omeprazole is superior to H₂ receptorantagonists regarding healing of gastroduodenal and esophageal lesionsas well as providing dyspeptic symtom resolution in these conditions.

The S-enantiomer of omeprazole, having the generic name esomeprazole, isrecently launched as a new generation of proton pump inhibitors.Esomeprazole shows further improvements in the treatment of GERD.

Omeprazole, i.e. the compound5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,and therapeutically acceptable salts thereof, are described in EP 5129.The specific alkaline salts of omeprazole are disclosed in EP 124 495.

Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atombeing the stereogenic center. Thus, omeprazole is a racemic mixture ofits two single enantiomers, the R- and S-enantiomer of omeprazole,herein referred to as R-omeprazole and S-omeprazole, the latter havingthe generic name esomeprazole. The absolute configurations of theenantiomers of omeprazole have been determined by an X-ray study of anN-alkylated derivative of the (+)-enantiomer in non-salt form. The(+)-enantiomer of the non-salt form and the (−)-enantiomer of thenon-salt form were found to have R and S configuration, respectively,and the (+)-enantiomer of the magnesium salt and the (−)-enantiomer ofthe magnesium salt were also found to have R and S configuration,respectively. The conditions for the optical rotation measurement foreach of these enantiomers are described in WO 94/27988.

Certain salts of single enantiomers of omeprazole and their preparationare disclosed in WO 94/27988. These compounds have improvedpharmacokinetic and metabolic properties, which will give an improvedtherapeutic profile such as a lower degree of interindividual variation.

WO 96/02535 discloses a process for the preparation of the singleenantiomers of omeprazole and salts thereof.

Proton pump inhibitors are susceptible to degradation/transformation inacid reacting and neutral media. In respect of the stability properties,it is obvious that the proton pump inhibitor must be protected fromcontact with acidic gastric juice by an enteric coating layer. There aredifferent enteric coating layered preparations of proton pump inhibitorsdescribed in the prior art, see for example U.S. Pat. No. 4,786,505 (ABHassle) and WO 96/01623 (Astra AB).

SUMMARY OF THE INVENTION

It has been found according to the invention that administration ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,having the generic name esomeprazole, to patients affected by sleepingdisturbance results in disappearance or great improvement of thesymptoms. This applies especially to patients with GERD.

Esomeprazole is a pharmaceutical agent having the formula

The active compound used according to the invention may be used inneutral form or in the form of an alkaline salt, such as for instancethe Mg²⁺, Ca²⁺, Na²⁺ or K⁺ salts, preferably the Mg²⁺ salts.

The chemical nameS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand pharmaceutically acceptable salts thereof does not necessarily meanthat the methoxy group of the benzimidazole moiety is in the 5-positionbut may as well be in the 6-position, or there may be mixtures of thetwo. This is due to equilibration in solution before the salts areformed in the solid state. The numbering is in accordance with the rulesfor nomenclature of organic chemistry, namely that the numbering of theatoms in the benzimidazole moiety should be done in such a way that thesubstituents should get the lowest possible number.

Esomeprazole can be administered orally, rectally or parenterally inneutral form or in the form of an alkaline or basic salt, such as forinstance the Mg²⁺, Ca²⁺, Na⁺, or K⁺ salts, preferably the Mg²⁺ or Na⁺salts.

The present invention is also applicable to other proton pump inhibitorcompounds such as for instance omeprazole, lansoprazole, pantoprazoleand rabeprazole.

While the effect on the symptoms of sleeping disturbance have beenestablished in patients who have taken esomeprazole by the oral route,it is believed that the improved effect of esomeprazole is a systemiceffect which is not dependent on what mode of administration that isused, and that accordingly the improved effect on sleeping and qualityof life will be seen also with other routes of administration such asrectal or parenteral administration.

The commercially available pharmaceutical formulations of esomeprazolewill normally be used also for treating sleeping disturbance andobtaining improved sleeping. Presently commercially availableformulations marked under the tradename Nexium are based on esomeprazolemagnesium salt in the form of enteric coating layered pellets filed in acapsule or multiple unit tablets comprising the same active ingredient.

Being a labile compound with poor storage stability at neutral or acidpH, esomeprazole formulations must be produced with great care. Examplesof ways of producing stable formulations are given in e.g. EP 247 983and EP 723 476.

The dose of esomeprazole to be administered in the treatment of sleepingdisorders to obtain an improvement in sleeping will vary depending onfactors such as the severity of the condition and the status of thepatient. The dosage range at oral, rectal as well as i.v. administrationmay be in the interval from 1 to 100 mg per day. Normally, an amount offrom 10 to 40 mg of esomeprazole daily and more preferred 20 mg and 40mg is envisaged at oral administration.

The invention is further exemplified by the following case studies.During oral treatment with esomeprazole for acid related diseases suchas non-erosive and erosive induced upper gastrointestinal disorders,evidence has accumulated that esomeprazole may be beneficial fortreatment of sleeping disturbance especially in patients with GERD andendoscopy negative GERD. Some examples are presented below:

OBJECTIVES: Endoscopy-negative gastroesophageal reflux disease (GERD)lacks objective markers of disease severity. Evaluation of therapies forGERD must therefore rely on subjective measures, including patientself-report questionnaires, to measure the clinical effectiveness oftherapeutic interventions. We aimed to evaluate the previously validatedGastrointestinal Symptoms Rating Scale (GSRS) and the Quality of Life inReflux and Dyspepsia (QOLRAD) questionnaires for reliability andresponsiveness to change over time.

METHODS: Patients (n=1143) with heartburn, but no esophagitis includedin a randomized clinical trial assessing the effectiveness of activetreatment with proton pump inhibitors over 4 wk were evaluated.

RESULTS: The test-retest reliability of both questionnaires over timewas good to excellent (GSRS 0.53-0.69; QOLRAD 0.65-0.76), as was theresponsiveness estimated by standardized response means (GSRS refluxdimension, −1.43; QOLRAD 0.81-1.43) and effect sizes (GRSR refluxdimension, −1.74; QOLRAD 0.82-1.56). The relationship betweenimprovement in the GSRS reflux dimension score and the amount ofclinical benefit as estimated by the patients themselves (based on theOverall Treatment Evaluation) suggested a minimally clinical relevantchange is 0.5 on the seven graded scales applied. The importance ratingindicated that an important change in the GSRS reflux dimension and theQOLRAD dimensions is equivalent to 1.0, and a very important change to1.5.

CONCLUSIONS: The GSRS and QOLRAD are valid questionnaires that arereliable and sensitive to change. Both questionnaires should be suitablefor use in clinical trials of therapeutic interventions for patientswith heartburn.

(Am J Gastroenterol 2001;96:1998-2004. © 2001 by Am. Coll. ofGastroenterology)

Patients and Methods

A total of 1143 male and female patients, aged 18 to 80 yr, identifyingtheir main symptom as a burning feeling rising from the stomach or thelower part of the chest up toward the neck (i.e., heartburn), werestudied. All patients were included in a multi-center, double-blind,randomized, parallel group study. They completed quality of lifequestionnaires at baseline and during follow-up at 2 and 4 wk. Allpatients were treated with proton pump inhibitors for 4 wk (esomeprazole20 mg daily, esomeprazole 40 mg daily, or esomeprazole 20 mg daily). Theeligibility criteria stated that patients with endoscopically verifiednormal esophageal mucosa, a history of episodes of heartburn for 6months or longer, and episodes of heartburn for 4 days or more duringthe last 7 days were eligible to enter the study. Excluded were patientswith symptoms likely to be caused by the irritable bowel syndromeaccording to the Manning criteria, as were patients with alarm symptoms(unintentional weight loss, hematemesis, melena, jaundice, or any othersign indicating serious or malignant disease), or current or historicalevidence of other gastrointestinal diseases and conditions (e.g.,Zollinger-Ellison syndrome, esophageal stricture, more than five gastricerosions during the past 2 yr, duodenal or gastric ulcers within thepast 2 yr, Barrett's metaplasia).

The two self-report questionnaires, GSRS and QOLRAD, were completed atbaseline and at 2 and 4 wk of treatment. In addition, an OverallTreatment Evaluation (OTE) was completed at 2 and 4 wk. The baselinequestionnaires were completed at the clinic before clinical examination.A standardized procedure for the administration of the questionnaireswas adhered to throughout the study. Demographic and clinicalcharacteristics were recorded in the Case Report Form as was severityand frequency of heartburn assessed by the clinician at baseline andduring follow-up.

Gastrointestinal Symptom Rating Scale (GSRS)

The GSRS was specifically developed to address symptoms important topatients with general gastrointestinal complaints and has beenextensively validated in previous studies (18, 20). The GSRS includes 15items addressing different gastrointestinal symptoms and uses a 7-pointLikert response scale with verbal descriptors. The response scale isdesigned to measure the amount of discomfort a patient has experienced(none at all, minor, mild, moderate, moderately severe, severe, and verysevere). A higher score in a GSRS cluster indicates more discomfort. Therecall period refers to the past week. The 15 items combine into fivesymptom clusters labeled: reflux, abdominal pain, indigestion, diarrhea,and constipation. The reflux dimension was identified as the mostrelevant dimension for the patient population in this study. Fromindividual items within a cluster, a mean score is calculated. The GSRShas been applied in patients with heartburn with and without esophagitis(21-24).

Quality of Life in Reflux and Dyspepsia (QOLRAD)

The QOLRAD was specifically developed to monitor changes inhealth-related quality of life in patients suffering from heartburn anddyspepsia. The development, initial psychometric documentation andcross-sectional validity have previously been presented (19). The QOLRADquestionnaire has 25 items with five clinically relevant domainsdepicting emotional distress, sleep disturbance, food and drinkproblems, physical/social functioning, and vitality. The recall periodrefers to the past week. A 7-point Likert response scale is used toassess how much or how often the item described the feelings of thepatient with respect to degree of distress (none at all, hardly any atall, a little, some, a moderate amount, a lot, a great deal) orfrequency of the problem (none of the time, hardly any of the time, alittle of the time, some of the time, quite a lot of the time, most ofthe time, all of the time). A higher score on the QOLRAD indicates lessfrequency in a domain. A mean score is calculated using items in eachdomain.

Overall Treatment Evaluation (OTE)

An anchor-based approach asking patients to provide a global rating ofperceived symptom change over time, was used to estimate the minimalclinically relevant change in the GSRS reflux dimension (17, 25, 26).The OTE was included as an independent measure of change, in order todetermine numerical changes in symptoms and health-related quality oflife. It has previously been used to clarify the clinical relevance ofchanges in health-related quality of life in clinical trials (27), andto justify the validity of what is considered to be a minimallyimportant change (28). The hierarchical scale first asks the patient,“Since treatment started, has there been any change in your symptoms ofheartburn or acid regurgitation?” resulting in a response of better,about the same, or worse. If the patient responded “better” or “worse”,the patient was asked to rate the degree of positive or negative changeusing a 7-point Likert scale, indicating how much better or worse theirconditions were (almost the same, hardly better/worse at all, changed alittle, somewhat, moderately, a good deal, a great deal, or a very greatdeal). In addition to the GSRS reflux dimension, the global rating ofsymptom change was also related to changes in the QOLRAD dimensions in asimilar fashion.

The OTE included a second question asking the patient to rate theimportance of the change if they answered better or worse to the firstquestion. The importance question which asked, “Is this change (better,worse) important to you in carrying out your daily activities?” utilizeda 7-point Likert scale to measure the degree of importance (not,slightly, somewhat, moderately, very, and extremely important).

Methodological Issues

RELIABILITY. In order for a symptom or quality of life questionnaire tobe reliable, the ratio of the variability in scores between patients tothe total variability—the reliability coefficient—should be ofacceptable magnitude, i.e., >0.60 (29-31). Non-responders were in thiscase defined as patients who had “no change” or “about the same, hardlybetter/worse at all” after the treatment period according to the OTE.Such an approach using non-responsive patients with heartburn to testthe stability of a questionnaire has been applied previously (20).

RESPONSIVENESS OR SENSITIVITY TO CHANGE. One fundamental attribute of ameasurement tool is its ability to detect changes in a patient'scondition over time. In order to demonstrate that a measure isresponsive to a treatment with known effectiveness, it must beadministered to patients over a given time period. Provided thetreatment is effective, patients should experience a change in theircondition as measured by disease-specific questionnaires. There is noconsensus regarding how best to assess the responsiveness to change.Hence, various approaches have been reported (24). The traditional waysof measuring responsiveness are to calculate 1) the effect size bydividing the mean change by the standard deviation at baseline (32 and2) the standardized response mean, which is the mean change divided bythe standard deviation of the change. This latter method preserves therelation to a statistical test, whereas the former anchors the changesagainst the variability in the sample.

Statistical Analysis

To evaluate reliability, the within patient and between patient meansquare were calculated by two-way analysis of variance (ANOVA) with thefactors of patients and week (baseline and 2 and 4 wk). The calculationused data from those patients who reported no change during the 4 wk oftreatment according to the OTE. The reliability coefficient is estimatedas:$R = \frac{{BMS} - {WMS}}{\left\lbrack {{BMS} + {\left( {K_{0} - 1} \right){WMS}}} \right\rbrack}$where BMS and WMS are the mean square values between patients and withinpatients, respectively, and K₀ denotes the number of repeated timemeasurements (33). The procedure PROC GLM within SAS was used for thecalculations. Values off R<0.4 may be taken to represent poorreliability, values >0.75 excellent reliability, and values in between,fair to good reliability (30, 33).

The clinical relevance was explored as change score correlation, usingPearson's correlation coefficient. This was done by correlating thechange from baseline to 4 wk for the clinician rating of severity andfrequency of heartburn with the change in the QOLRAD domains.

The perceived change according to the OTE was classified as none, small,moderate, and large (26). This system classifies patients who were aboutthe same or “almost the same, hardly better/worse at all” as unchanged,those patients indicating a little or somewhat better/worse areclassified as having a small OTE change, those indicating moderately ora good deal better/worse, as having a moderate OTE change, and thoseindicating a great deal or very great deal better/worse, as having alarge OTE change (28). This collapsed OTE scale was given scores from −3(for large negative change) to 3 (for large positive change) with zerofor unchanged patients. Linear regression was used to determine thechange in each dimension corresponding to a one unit change in thecollapsed OTE scale. The change for the GSRS reflux cluster, which isdirectly related to the symptoms under treatment, is taken to representa minimally relevant change.

The patient importance rating of change was determined by comparing theGSRS clusters and QOLRAD domains to the OTE importance scale. Wecollapsed the importance rating into 4 classifications: not important(not important), slight/moderately important (slightly, somewhat, ormoderately important), important (important), and very important (veryor extremely important).

Results

Patients characteristics and clinical data are summarized in Table 1.The severity of heartburn was on average moderate, with over 50% of thepatients having daily symptoms, and almost half having a duration ofsymptoms >5 yr.

Reliability

The evaluation of reliability utilized the 73 patients who reported nochange at both 2 and 4 wk of treatment. Table 2 shows the estimatedreliability (intraclass correlation coefficients) for the GSRS clustersand the QOLRAD domains. Reliability ranged from 0.53 to 0.69 for theGSRS and 0.65 to 0.76 for the QOLRAD. Using predefined criteria, thereliability was good to excellent for most scales.

Change Score Correlations

The correlations between the change in the clinicians rating of severityand frequency of heartburn and the change in the QOLRAD domains arepresented in Table 3. All correlations indicated a moderate relationshipbetween relief of heartburn and improved quality of life. At 4 wk, therange was from 0.27 to 0.50 (p<0.0001). The correlations at 2 wk werevery similar (data not shown). TABLE 1 Demographic and ClinicalCharacteristics at Baseline Age (yr), mean (SD) 48.3 (14.0) Age (yr)16-50 57* 51-60 20 61-80 23 Gender, males 44 Race, caucasian 98Employed/self-employed, yes 59 Clinician rated frequency of heartburn  4days/wk 24 5-6 days/wk 20  7 days/wk 56 Clinician rated severity ofheartburn Mild 22 Moderate 59 Severe 18 History of heartburn <12 mo 121-5 yr 39  >5 yr 48Patients with both a baseline and a subsequent visit (a - I 143).*All values in this column are percentages.Responsiveness

Table 4 presents the standardized response mean and the effect size at 4wk for the GSRS and QOLRAD. The standardized response mean showed that,in addition to the GSRS reflux dimension, sizeable changes were alsodetected in the abdominal pain and indigestion dimensions. As expected,the responsiveness of the GSRS to constipation and diarrhea was lower.The responsiveness of the QOLRAD was excellent in all dimensions, inparticular with regard to food and drink problems. Effect sizes werealmost identical to the standardized response means for bothquestionnaires (Table 4). The results were very similar at 2 wk (datanot shown).

The effect size was large for GSRS reflux and for all of the QOLRADdomains according to the definition of Cohen, which states that aneffect size ≧0.5 indicates moderate sensitivity and an effect size of0.8 indicates a large responsiveness to change (32).

Minimally Relevant Change

The changes in GSRS symptom clusters and QOLRAD domains in relation tothe magnitude of the perceived improvement as defined by the OTE arepresented in Table 5. TABLE 2 Test-Retest Reliability IntraclassCorrelation Coefficient (ICC) in Patients Reporting No Change Accordingto the Overall Treatment Evaluation (OTE) ICC ICC GSRS (n = 73) QOLRAD(n = 73) Diarrhea 0.69 Emotional distress 0.75 Indigestion 0.65 Sleepdisturbances 0.76 Constipation 0.60 Food/drink problems 0.76 Abdominalpain 0.53 Physical/social functioning 0.76 Reflux 0.59 Vitality 0.65

TABLE 3 Change Score Corre1ations: Change in Clinician Rated Severityand Frequency of Heartburn, and Change in QOLRAD Total and DimensionScores* Severity Frequency (n = 1108) (n = 1108) QOLRAD r Value r ValueEmotional distress 0.43 0.34 Sleep disturbances 0.41 0.30 Food/drinkproblems 0.50 0.47 Physical/social functioning 0.39 0.27 Vitality 0.440.39All correlations p < 0.0001.r value Pearson correlation coefficient.*Baseline to 4 wk.

The difference between adjacent OTE classes (small no change,moderate-small change, or large-moderate change) was approximately 0.5score units for the GSRS reflux dimension (scale from 1-7). Thissuggests a minimally relevant change of 0.5. The QOLRAD exhibitedsimilar results for all dimensions with the exception of thephysical/social domain. The results were very similar at 2 wk (data notshown).

Table 6 shows the estimated change in GSRS reflux dimension and QOLRADdomains compared to a one-unit improvement in the collapsed OTEclassification. All changes were statistically significant at the p<0.05level. The change for the GSRS reflux dimension was 0.51 at 4 wk. Thissupports 0.5 as an approximate value for a minimally relevant is change.The results were also very similar at 2 wk (data not shown).

Patient Importance Rating of Change

Table 5 shows the change in GSRS and QOLRAD scores from baseline to 4 wkby the patient's rating of the importance of the change for carrying outdaily activities as defined by the OTE. For the GSRS reflux dimensionand for the QOLRAD dimensions, the change scores showed a consistenttrend with increasing importance rating. An important change as definedby the patients equals approximately I score unit change in the QOLRADdimensions, and in the GSRS reflux dimension. The results were similarat 2 wk (data not shown). TABLE 4 Standardized Response Mean (SRM) andEffect Sizes at 4 Weeks Effect Effect GSRS SRM (SD of change) SizeQOLRAD SRM (SD of change) Size Diarrhea −0.15 (1.15) −0.16 Emotionaldistress 1.24 (1.48) 1.25 Indigestion −0.86 (1.24) −0.83 Sleepdisturbances 1.13 (1.46) 1.12 Constipation −0.37 (1.10) −0.34 Food/drinkproblems 1.43 (1.43) 1.56 Abdominal pain −0.87 (1.19) −0.93Physical/social func. 0.81 (1.24) 0.82 Reflux −1.43 (1.45) −1.74Vitality 1.24 (1.51) 1.45Discussion

Evaluations of health-related quality of life facilitate a translationof clinical benefits into outcomes of significance to patients. Inpatients with symptomatic heartburn without esophagitis, the evaluationof new therapies relies entirely upon subjective patient-based outcomes.There is no independent way of deriving confirmation of the degree ofdistress and dysfunction induced by symptoms. Standardized methods thataddress symptoms and health-related quality of life must therefore beused to monitor the patient's response to treatment. The development ofsubjective selfreport questionnaires for symptoms and quality of lifeassessment requires rigorous psychometric evaluation if theseinstruments are to be confidently used to assess treatment efficacyendpoints in clinical trials of new therapeutics (34-36). Traditionally,psychometric documentation has been limited to cross-sectional issues ofitem selection and domain construction, with the resulting domainintercorrelations, internal consistency, reliability, convergentvalidity, and discriminant validity. Although cross-sectional validityis a necessary precondition to the use of a questionnaire, it does notguarantee that the instrument will perform well when used in an actualclinical trial setting. Neither does it guarantee that the instrumentwill be able to detect changes that patients rate as significant. Thus,less attention has been paid to the psychometric documentation oftest-retest reliability and responsiveness to change despite the factthat the latter feature in particular is crucial to an instrument'sutility in clinical trials (37, 38).

This study was not ideal for assessing reliability owing to therelatively small proportions of patients who did not respond totreatment. Strictly, the estimated reliability applies only to thislimited group of non-responding patients. However, the baseline samplevariances for the non-responders were similar to the correspondingbaseline sample variances for the whole study population. Thus, assumingthe within patient variances for non-responders are representative forthe study population, the reliability estimates should be applicable tothe patient group under study. The reliability coefficients did suggestthat the GSRS and QOLRAD are reliable instruments, as has beenpreviously documented using similar technique (20).

Two different measures—the standardized response mean and the effectsize used to assess responsiveness—yielded similar results, documentingthe responsiveness of both questionnaires. The magnitude of theestimated responsiveness reflects the know efficacy of the treatment(i.e., in this case, treatment of symptomatic heartburn with proton pumpinhibition). In another study, the effect size at 4 wk of treatment withproton pump inhibitors in the GSRS reflux dimension was 1.2 compared to0.5 observed in the placebo aim, indicating a large effect (21). Asexpected, the responsiveness was lower for symptom clusters notassociated with heartburn (i.e., symptoms of the lowergastrointestinaltract). TABLE 5 Changes in GSRS and QOLRAD DimensionScores From Baseline to 4 Weeks by Patient Rating of the Magnitude ofthe Change As Well As the Importance of the Change. Importance RatingSlight/ Change Rating Not Moderately Very None Small Moderate LargeImportant Important Important Important GSRS Dimension n = 133 n = 69 n= 171 n = 702 n = 171 n = 150 n = 183 n = 567 Diarrhea −0.01 (1.23)  0.04 (1.18) −0.32 (1.04) −0.23 (1.11) −0.09 (1.19)   0.17 (1.07) −0.17(1.01) −0.26 (1.16) Indigestion −0.60 (1.12) −0.78 (0.97) −1.04 (1.16)−1.23 (1.24)   0.65 (1.13) −0.90 (1.22) −0.95 (1.13) −1.31 (1.23)Constipation −0.24 (1.32) −0.38 (1.01) −0.37 (0.99) −0.48 (1.08) −0.31(1.25) −0.38 (1.01) −0.42 (1.07) −0.47 (1.07) Abdominal/ −0.66 (1.20)−0.65 (1.01) −0.82 (1.02) −1.27 (1.14) −0.74 (1.16) −0.87 (1.03) −0.99(1.11) −1.27 (1.16) Pain Reflux −0.99 (1.31) −1.59 (1.22) −1.68 (1.24)−2.51 (1.29) −1.20 (1.33) −1.88 (1.19) −2.13 (1.35)   2.47 (1.34) QOLRADDimension n = 140 n = 71 n = 175 n = 721 n = 178 n = 159 n = 191 n = 580Emotional   0.83 (1.18)   1.51 (1.32)   1.78 (1.23)   2.18 (1.43)   0.93(1.17)   1.47 (1.20)   1.72 (1.18)   2.37 (1.44) Sleep   0.75 (1.17)  1.41 (1.31)   1.63 (1.23)   1.94 (1.43)   0.88 (1.24)   1.37 (1.23)  1.57 (1.17)   2.09 (1.45) Food/drink   0.85 (1.11)   1.35 (1.20)  1.78 (1.10)   2.50 (1.32)   1.02 (1.17)   1.83 (1.10)   1.93 (1.16)  2.57 (1.37) Phys/soc   0.35 (0.93)   0.79 (1.27)   1.00 (1.02)   1.24(1.22)   0.41 (0.92)   0.73 (0.93)   0.92 (1.03)   1.40 (1.26) Vitality  0.77 (1.31)   1.34 (1.30)   1.58 (1.29)   2.32 (1.38)   0.97 (1.34)  1.69 (1.20)   1.74 (1.43)   2.38 (1.39)Change rating and importance rating expressed as change in the mean(SD).

TABLE 6 Estimated Change in GSRS Reflux Dimension and QOLRAD Scores Dueto One-Unit Improvement in Collapsed Overall Treatment Evaluation*. GSRSDimension Estimate (STD error) Reflux −0.51 (0.03) QOLRAP DimensionsEstimate (STD error) Emotional distress 0.45 (0.03) Sleep disturbances0.41 (0.03) Food/drink problems 0.54 {0.03) Physical/social functioning0.33 (0.03) Vitality 0.51 {0.03)*No change, small moderate, and large improvement at 4 wk.

The determination of the minimally clinical relevant change in clinicaltrials is a critical issue (17, 30, 38, 39). We based our analysis onthe method employed by Juniper (26) and found that a minimal clinicallyrelevant change was 0.5. This is consistent with findings for otherinstruments utilizing 7-point Likert scale, where the minimallyimportant change has been estimated to be 0.5 unit (26, 28, 40), while achange score of approximately 1-5 units represented a large change inquality or life (26). One possible criticism of the approach taken inthe present study was the selection of cut-off points used to classifythe OTE effect. However, others have used similar modified approaches(17, 41).

Large change scores were found for the GSRS reflux dimension, and all ofthe QOLRAD domains. The observed changes were smaller in thephysical/social dimension of QOLRAD. This is not surprising, becausehalf of the patients had suffered from heartburn for 5 yr or more. Witha long duration of disease, patients may adapt to their situation byavoiding activities that provoke symptoms (42). Compared with the effectsizes for antihypertensive therapy, which range from 0.01 to 0.3 (43),the present findings show, that large changes in the direction of bettercan be detected.

Beyond the evaluation of clinical relevant change is the question of theimportance of a change to the patient. The patient must be the personthat determines what is important to them, because the agreement betweenclinician and patient ratings of health-related quality or life isusually poor (44). This is one of the first studies that has tried tolink what patients perceive as an important change in symptoms tochanges in quality of life, an issue that is particularly pertinent inGERD where the evaluation of treatment effect relies on patientreporting. Thus, the effects of therapy on symptom relief andhealth-related quality of life are important considerations in thetreatment of patients with symptomatic heartburn and should beconsidered as primary end-points in clinical trials in this patientpopulation.

The association between relief of symptoms and health-related quality oflife was studied by correlating the change in reflux symptoms rated bythe clinician with the change in health-related quality of life asmeasured by the patient. There was a clear relationship between symptomresolution and improvement in QOLRAD domains, which supports theclinical validity of the health-related quality of life instrument. Foodand drink problems, which may be related to acid secretion, were moststrongly correlated with symptom relief. These findings suggest that thesymptomatic benefits of treatment are directly reflected by an enhancedhealth-related quality of life. Both the GSRS reflux dimension and theQOLRAD have good reliability and are responsive to change in symptomaticheartburn. For these questionnaires, it is possible to quantify aminimally relevant change as well as the importance of change scores.

1. A method for treatment of sleeping disturbance, wherein the methodcomprises administering a therapeutically effective amount ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(esomeprazole) or a pharmaceutically acceptable salt thereof to apatient in need thereof.
 2. A method for improving sleep in a patientsuffering from gastroesophagal reflux disease, wherein the methodcomprises administering a therapeutically effective amount ofS-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(esomeprazole) or a pharmaceutically acceptable salt thereof a patientin need thereof.
 3. The method according to any one of claims 1 or 2,wherein the esomeprazole is administered in the form of an alkaline saltselected from the group consisting of Mg²⁺, Ca²⁺, Na²⁺ and K²⁺ salts. 4.The method according to any one of claims 1 or 2, wherein the salt is amagnesium salt.
 5. The method according to one any of claims 1 or 2,wherein the salt is a magnesium salt.
 6. The method according to any oneof claims 1 or 2, wherein the esomeprazole or an alkaline salt thereofis administered orally.
 7. The method according to any one of claims 1or 2, wherein the esomeprazole or an alkaline salt thereof isadministered parenterally.
 8. The method according to any one of claims1 or 2, wherein the esomeprazole or an alkaline salt thereof isadministered in a dose of from 1 to 100 mg daily.
 9. The methodaccording to claim 8, wherein the esomeprazole or the alkaline saltthereof is administered in a dose of from 10 to 40 mg daily. 10.(canceled)
 11. (canceled)